Mitoxantrone ameliorates ineffective erythropoiesis in a ß-thalassemia intermedia mouse model.

ß-thalassemia is a condition characterized by reduced or absent synthesis of ß-globin resulting from genetic mutations, leading to expanded and ineffective erythropoiesis. Mitoxantrone has been widely used clinically as an antitumor agent in light of its ability to inhibit cell proliferation. However, its therapeutic effect on expanded and ineffective erythropoiesis in ß-thalassemia is untested. We found that mitoxantrone decreased α-globin precipitates and ameliorated anemia, splenomegaly and ineffective erythropoiesis in the HbbTh3/+ mouse model of ß-thalassemia intermedia. The partially reversed ineffective erythropoiesis is a consequence of effects on autophagy as mitochondrial retention and protein levels of mTOR, P62 and LC3 in reticulocytes decreased in mitoxantrone-treated HbbTh3/+ mice. These data provide significant pre-clinical evidence for targeting autophagy as a novel therapeutic approach for ß-thalassemia.

Histone acetyltransferase CSRP2BP promotes the epithelial-mesenchymal transition and metastasis of cervical cancer cells by activating N-cadherin.

BACKGROUND: Dysregulated epithelial-mesenchymal transition (EMT) is involved in cervical cancer metastasis and associated with histone acetylation. However, the underlying molecular mechanisms of histone acetylation in cervical cancer EMT and metastasis are still elusive. METHODS: We systematically investigated the expression patterns of histone acetylation genes and their correlations with the EMT pathway in cervical cancer. The expression of CSRP2BP among cervical cancer tissues and cell lines was detected using Western blotting and immunohistochemistry analyses. The effects of CSRP2BP on cervical cancer cell proliferation and tumorigenicity were examined by cell growth curve, EdU assay, flow cytometry and xenotransplantation assays. Wound healing assays, transwell migration assays and pulmonary metastasis model were used to evaluate the effects of CSRP2BP on cell invasion and metastasis of cervical cancer cells in vivo and in vitro. RNA-seq, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP) and luciferase reporter assays were used to uncover the molecular mechanisms of CSRP2BP in promoting cervical cancer EMT and metastasis. RESULTS: We prioritized a top candidate histone acetyltransferase, CSRP2BP, as a key player in cervical cancer EMT and metastasis. The expression of CSRP2BP was significantly increased in cervical cancer tissues and high CSRP2BP expression was associated with poor prognosis. Overexpression of CSRP2BP promoted cervical cancer cell proliferation and metastasis both in vitro and in vivo, while knockdown of CSRP2BP obtained the opposite effects. In addition, CSRP2BP promoted resistance to cisplatin chemotherapy. Mechanistically, CSRP2BP mediated histone 4 acetylation at lysine sites 5 and 12, cooperated with the transcription factor SMAD4 to bind to the SEB2 sequence in the N-cadherin gene promotor and upregulated N-cadherin transcription. Consequently, CSRP2BP promoted cervical cancer cell EMT and metastasis through activating N-cadherin. CONCLUSIONS: This study demonstrates that the histone acetyltransferase CSRP2BP promotes cervical cancer metastasis partially through increasing the EMT and suggests that CSRP2BP could be a prognostic marker and a potential therapeutic target for combating cervical cancer metastasis.

Intracranial complete response to toripalimab and anlotinib in a patient with recurrent brain metastases of small cell lung cancer after failure of second-line maintenance therapy: a case report.

Background: Approximately 10-25% of patients with small cell lung cancer (SCLC) have brain metastases at the time of diagnosis. Radiotherapy is a common treatment for brain metastases, but the relapse rates are high. Accumulating evidence suggests that immunotherapy may have a better therapeutic effect for brain metastases. Here, we reported a patient with limited-stage SCLC and relapsed brain metastases who achieved sustained intracranial complete response (CR) to programmed cell death-1 (PD-1) inhibitor toripalimab and multikinase inhibitor anlotinib. Case Description: A 59-year-old female patient developed brain metastases after initial treatment for limited stage SCLC. CR of brain lesions was achieved after intensity-modulated radiation therapy followed by chemotherapy with irinotecan plus lobaplatin and concurrent anlotinib. PD-1 inhibitor sintilimab combined with anlotinib were given as maintenance therapy. Small and asymptomatic brain lesions relapsed 2.5 months after achieving CR. Another three cycles of sintilimab combined with anlotinib failed to control the relapsed brain lesions. Following two cycles of another PD-1 inhibitor toripalimab combined with anlotinib, the relapsed brain metastases disappeared. Then the patient received another seven cycles of this regimen with sustained CR, and no serious adverse reactions occurred. Interestingly, the primary lung tumor achieved sustained CR from the end of initial treatment to the last follow-up. Conclusions: This case suggests that toripalimab in combination with anlotinib may be a promising treatment option for patients with brain metastases from SCLC.

Long non-coding RNA NNT-AS1 regulates proliferation, apoptosis, inflammation and airway remodeling of chronic obstructive pulmonary disease via targeting miR-582-5p/FBXO11 axis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a kind of chronic lung disease that mainly induced by smoking-caused inflammation. Long non-coding RNAs (lncRNAs) have been reported to play a part in the course of pulmonary diseases. Here, we studied the role of lncRNA NNT-AS1 in the development of COPD. MATERIALS: qRT-PCR analysis and ELISA assay were applied to evaluate the expression of genes and inflammatory cytokines, respectively. CCK8 and EdU assays were utilized to assess proliferation, while flow cytometry assay was conducted to evaluate apoptosis. Luciferase reporter, RNA pull down and RIP assays were combined to explore relationships between genes. RESULTS: NNT-AS1 was observed to be up-regulated in cigarette smoke extract (CSE)-treated 16HBE cells. Knockdown of NNT-AS1 abolished CSE-caused suppressive effects on cell proliferation, apoptosis, inflammation and airway remodeling. Mechanistically, NNT-AS1 up-regulated FBXO11 expression via sponging miR-582-5p. Moreover, miR-582-5p inhibitor or FBXO11 overexpression counteracted NNT-AS1 silence-elicited effects on proliferation, apoptosis, inflammation and airway remodeling. CONCLUSION: Our data revealed that NNT-AS1 played a promoting role in smoking-induced COPD via modulating miR-582-5p/FBXO11 signaling, suggesting a novel potential target for COPD treatment.

Identification and characterization of a Streptococcus suis immunogenic ornithine carbamoytransferase involved in bacterial adherence.

BACKGROUND: Streptococcus suis (SS) is a major swine pathogen and a serious zoonotic pathogen causing septicemia and meningitis in piglets and humans. Using an immunoproteomic approach, we previously brought evidence that ornithine carbamoytransferase (OCT) may represent a vaccine candidate to protect against S. suis biofilm-related and acute infections. METHOD: In this study, the gene encoding OCT was cloned into the expression vector pET-28a and the recombinant protein was expressed in Escherichia coli BL21. The immunogenicity and protective efficacy of the SS OCT was further investigated in a mouse model. RESULTS: The protein was found to be expressed in vivo and elicited high antibody titers following SS infections in mice. An animal challenge experiment with SS showed that 62.5% of mice immunized with the OCT protein were protected. Using an in vitro competitive adherence inhibition assay of adherence, evidence was obtained that OCT could significantly reduce the number of SS cells adhered to porcine kidney PK-15 cells. The bacterial levels recovered in mice of the OCT immunized group were significantly decreased in some organs, compared with the control group. CONCLUSION: In summary, our results suggest that the recombinant SS OCT protein, which is involved in bacterial adherence, may efficiently stimulate an immune response conferring protection against SS infections. It may therefore be considered as a potential vaccine candidate, although further studies are necessary to evaluate their use in swine.

Chemical Vapor Deposition Method Grown All-Inorganic Perovskite Microcrystals for Self-Powered Photodetectors.

Self-powered photodetectors (SPPDs) have attracted lots of attention due to their various advantages including no external power sources, high-sensitivity, fast response speed, and so on. This study reports the fabrication and characterization results of CsPbBr3 microcrystals (MCs) grown by chemical vapor deposition (CVD) method, and the SPPDs have been fabricated on the basis of the CsPbBr3 MCs layer with the sandwich structure of GaN/CsPbBr3 MCs/ZnO. Such designed SPPD shows the detectivity ( D*) of 1014 Jones, on/off ratio of up to 105, peak responsivity ( R) of 89.5 mA/W, and enhanced stability at the incident wavelength of 540 nm. The photodetector enables the fast photoresponse speed of 100 µs rise time and 140 µs decay time. The performances of the SPPD are comparable to the best ones ever reported for CsPbBr3 based PDs but do not need external power supplies, which mainly benefit from the low trap density, long carrier diffusion of high quality CsPbBr3MCs film, and the built-in electric fields in the sandwich structure of GaN/CsPbBr3/ZnO layers.

High-Efficient Excitation-Independent Blue Luminescent Carbon Dots.

Blue luminescent carbon dots (CDs) were synthesized by the hydrothermal method. Blue-shifts of the maximum emission wavelength from 480 to 443 nm were observed when the concentration of CD solution decreased. The photoluminescence (PL) spectra of CDs at low concentration showed an excitation-independent behaviour, which is very different from the previous reports. Two different emitting mechanisms might work: the intrinsic luminescence from sp2-carbon networks can be responsible for the shorter wavelength part of emission (excitation-independent) at low concentration and the high polarity of nanosized clusters led to the excitation-dependent behaviour of the longer wavelength part at high concentration of CD solution. The photophysical property and concentration-dependent behaviour of the CDs offered new insights into CDs from the viewpoints of both experiments and mechanisms, which will promote diverse potential applications of CDs in the near future.

Whispering Gallery Mode Laser from Carbon Dot-NaCl Hybrid Crystals.

Carbon dot (CD)-NaCl hybrid crystals are obtained by incorporating the CDs into NaCl matrix through a simple process. The embedded CDs have added the luminescence centers into NaCl, and as a result, the hybrid crystals present the fluorescence centered at 510 nm under the illumination of 365 nm light. Meanwhile, the phosphorescence with an average lifetime of 314 ms is achieved after the 365 nm light was turned off. Furthermore, optical gain and lasing phenomenon has been observed from hybrid crystals. When the pump power is low, a weak spontaneous emission can be observed from the hybrid crystal, whereas the lasing action was observed under high pump power. The lasing threshold is found to be 0.08 mW and corresponding Q factor is calculated to be 447. The tiny cubic crystal in hybrid crystals offers the whispering gallery mode (WGM) resonant cavity for lasing emission. That has provided a new approach for realizing lasing materials.

The preventive effects of hyperoside on lung cancer in vitro by inducing apoptosis and inhibiting proliferation through Caspase-3 and P53 signaling pathway.

Though advanced surgical operation and chemotherapy have been under taken, lung cancer remains one of the most aggressive and fatal human malignancies with a low survival rate. Thus, novel therapeutic strategies for prevention and remedy are urgently needed in lung cancer. Hyperoside, known as quercetin-3-O-ß-d-galactopyranoside, is a natural flavonol glycoside discovered in plants of genera Hypericum, displaying anti-oxidant, anticancer, and anti-inflammatory properties. In the study, we attempted to investigate whether hyperoside could inhibit lung cancer progression via Caspase-3- and P53-regulated cell death. In in vitro and in vivo experiments, we explored hyperoside at three different dosages on cell apoptosis, cell proliferation, cell migration, cell invasion, cell cycle distribution, the related signalling pathways, as well as xenograft tumor growth. Our data suggested that hyperoside exerted inhibitory role in lung cancer development. Inhibition of NF-κB transcriptional activity, Caspase-9/Caspase-3 activation, the cell cycle arrest, and suppression of cell proliferation-related signaling pathway led to the lung cancer inhibition. Further, via mice xenograft model in vivo, we indicated that hyperoside completely impeded tumor growth through angiogenesis inhibition. Our study illustrated that hyperoside might provide a synergistic anticancer effects that warrant further study and investigation due to its potential role in clinical applications.

Fast Photoconductive Responses in Organometal Halide Perovskite Photodetectors.

Inorganic semiconductor-based photodetectors have been suffering from slow response speeds, which are caused by the persistent photoconductivity of semiconductor materials. For realizing high speed optoelectronic devices, the organometal halide perovskite thin films were applied onto the interdigitated (IDT) patterned Au electrodes, and symmetrical structured photoconductive detectors were achieved. The detectors were sensitive to the incident light signals, and the photocurrents of the devices were 2-3 orders of magnitude higher than dark currents. The responsivities of the devices could reach up to 55 mA W(1-). Most importantly, the detectors have a fast response time of less than 20 µs. The light and bias induced dipole rearrangement in organometal perovskite thin films has resulted in the instability of photocurrents, and Ag nanowires could quicken the process of dipole alignment and stabilize the photocurrents of the devices.

A significant cathodic shift in the onset potential and enhanced photoelectrochemical water splitting using Au nanoparticles decorated WO3 nanorod array.

Au nanoparticles decorated WO3 nanorod array was prepared and applied for solar water oxidation. Scanning electron microscopy and transmission electron microscop images showed that Au distributed on the surface of WO3 nanorod array. The surface plasmon resonance effect of Au nanoparticles contributed to the enhancement of photoelectrochemical performance of Au-WO3 photoanode, such as enhanced photocurrent density of 1.17mA/cm(2) at 1.0V vs Ag/AgCl, a cathodic shift of onset of ∼0.2V and higher stability. UV-vis absorption, electrochemical impedance and Mott-Schottky measurements proved that Au-WO3 photoanode has enhanced light absorption, lower transfer resistance, increased photogenerated carriers density and higher hole injection yield. Therefore, Au-WO3 photoanode exhibited higher photoelectrochemical performance than WO3 photoanode.

Fabrication of highly interconnected porous silk fibroin scaffolds for potential use as vascular grafts.

Silk fibroin (SF) scaffolds have been designed and fabricated for multiple organ engineering owing to SF's remarkable mechanical property, excellent biocompatibility and biodegradability, as well as its low immunogenicity. In this study, an easy-to-adopt and mild approach based on a modified freeze-drying method was developed to fabricate a highly interconnected porous SF scaffold. The physical properties of the SF scaffold, including pore morphology, pore size, porosity and compressive modulus, could be adjusted by the amount of ethanol added, the freezing temperature and the concentration of SF. Fourier transform infrared spectroscopy illustrated that treatment of the lyophilized scaffolds with 90% methanol led to a structure transition of SF from silk I (random coil) to silk II (beta-sheet), which stabilized the SF scaffolds in water. We also incorporated heparin during fabrication to obtain a heparin-loaded scaffold which possessed excellent anticoagulant property. The heparin that was incorporated into the SF scaffolds could be released in a sustain manner for approximately 7days, inhibiting the proliferation of human smooth muscle cells within the scaffold in vitro while promoting neovascularization in vivo. We therefore propose that the SF porous scaffold fabricated here may be an attractive candidate for use as a potential vascular graft for implantation based on its high porosity, excellent blood compatibility and mild fabrication process.

[Association between interleukin-1B polymorphisms and chronic obstructive pulmonary disease: a meta-analysis].

OBJECTIVE: To explore the association between the -511C/T, -31T/C and +3954C/T polymorphisms of interleukin-1B (IL-1B) gene and chronic obstructive pulmonary disease (COPD) using the method of meta-analysis. METHODS: Comprehensive searches were performed of PubMed, Embase, Ovid, Wanfang and Chinese journal full-text database to retrieve the related case-control studies. The pooled odds ratios were performed respectively for allele comparison, additive genetic model, dominant genetic model and recessive genetic model and subgroup analysis was also performed by ethnicity. RESULTS: Seven case-control studies were included for meta-analysis. Pooled analysis showed that neither -511C/T, -31T/C nor +3954 C/T polymorphisms increased the susceptibility to COPD. In the subgroup analysis by ethnicity, significant risks were found in the Caucasian population for -511C/T T allele (OR = 1.76, 95%CI 1.22 - 2.54, P = 0.002), but not in the Asian population (OR = 0.94, 95%CI 0.64 - 1.38, P = 0.736). Significant risks were also found in the Caucasian population for -31T/C C allele (OR = 0.62, 95%CI 0.40 - 0.97, P = 0.035), but not in the Asian population (OR = 1.06, 95%CI 0.89 - 1.26, P = 0.533). CONCLUSIONS: IL-1B polymorphisms may play a role in the susceptibility of COPD in an ethnicity-specific manner. In the Caucasian population, the risk of COPD was associated positively with the IL-1B -511C/T T allele and negatively with the IL-1B -31T/C C allele.

Chronic obstructive pulmonary disease assessment test score correlated with dyspnea score in a large sample of Chinese patients.

BACKGROUND: The chronic obstructive pulmonary disease assessment test (CAT) is an easy to use health-related quality of life questionnaire, the modified Medical Research Council (mMRC) dyspnea scale is a classic dyspnea scale which is widely used, while the correlation between them is still not clear. This study investigated the use of the Chinese translation of CAT in chronic obstructive pulmonary disease patients and its correlation with the mMRC dyspnea scale. METHODS: The multicenter cross-sectional study was conducted in 329 hospitals throughout China from March 1 to April 30, 2010. Chronic obstructive pulmonary disease patients completed both the assessment test and the dyspnea scale during a single study visit. RESULTS: Six thousand, four hundred and thirty-seven patients were evaluated; 74.9% were male and the mean age was (64.9 ± 10.0) years. Median test scores in dyspnea grades 0 to 4 were 14, 16, 22, 26 and 32, respectively; these differences were statistically significant. The CAT score was moderately correlated with mMRC dyspnea grade (r = 0.579, P < 0.001). There was no significant difference in mean CAT score between males and females, and patients of high and low socioeconomic status. Primary analysis suggested that CAT scores were higher in older patients (>65 years) than in younger patients (≤ 65 years) and increased with duration of formal education, but these findings were repudiated by further analysis of subgroups according to mMRC dyspnea grade. CONCLUSIONS: There was no obvious confounding factor influencing use of the CAT in Chinese patients. CAT scores were moderately correlated with the mMRC dyspnea scale.

Expression, purification, and characterization of recombinant human soluble BAFF secreted from the yeast Pichia pastoris.

The B lymphocyte stimulator (BAFF) is a novel member of the tumor necrosis factor (TNF) ligand family which is important in B lymphocyte maturation and survival. Herein, the cDNA coding for the extracellular domain of the BAFF (hsBAFF) has been cloned into the secreting expression organism Pichia pastoris. SDS-PAGE and Western blotting assays of culture broth from a methanol-induced expression strain demonstrated that recombinant hsBAFF, a 20.2 kDa glycosylated protein, was secreted into the culture medium. The recombinant protein was purified to greater than 95% using DEAE-Sepharose ion exchange and Superdex 75 size-exclusion chromatography steps. Finally, 102 mg of the protein was obtained in high purity from 1 L of the supernatant and its identity to hsBAFF was confirmed by NH(2)-terminal amino acid sequence analysis Bioactivity of the recombinant hsBAFF was confirmed by the ability of the protein to stimulate human B lymphocyte proliferation in vitro. Our results suggest that the P. pastoris expression system can be used to produce large quantities of fully functional hsBAFF for both research and industrial purpose.